We have established that the expression of genes for critical virulence attributes of Streptococcus mutans, including those involved in biofilm formation, carbohydrate transport, acid production, catabolism of storage polymers, and exopolysaccharide production, is dramatically affected by exposure to oxygen. Moreover, we have disclosed complex control circuits for remodeling of the cell surface in response to redox, some of which we have shown to be centrally regulated by a two- component system and autolysin. The goals of this proposal are to understand the phenotypic consequences of growth of S. mutans in the presence of oxygen and to dissect the underlying molecular basis for our observations that S. mutans is a radically different organism when cultured in air. To achieve these goals, the following Specific Aims are established. Aim 1. Comparison of virulence-related phenotypic properties of cells cultured anaerobically or aerobically Aim 2. Comparison of the surface and secretome of cells cultured anaerobically or aerobically Aim 3. Analysis of cis- and trans-acting elements of O2-responsive genes By implementing the Research Plan for these aims, a comprehensive understanding of the responses of S. mutans to air and anaerobiosis will be realized. These studies will lead directly to a better understanding of the behavior of this pathogen in immature and mature dental plaque. This line of investigation has already discovered, and will continue to disclose, novel pathways that may serve as targets to disrupt the establishment and persistence of S. mutans. The proposed studies are broadly relevant and will facilitate the development of new therapy to combat dental caries and other diseases. PUBLIC HEALTH RELEVANCE: We have discovered that the primary causative agent of human dental caries, Streptococcus mutans, undergoes major changes in gene expression and dramatically remodels its surface in response to exposure to oxygen. The goals of this research are to understand how these changes affect the ability of this organism to colonize, persist and cause disease, and to dissect the underlying regulatory pathways that effect these changes. The knowledge generated from these studies will lead directly to new strategies to control dental caries and will provide much-needed insight into how other medically-important pathogens alter their appearance and behavior to cause diseases.